Halogen Bonding in Sulphonamide Co-Crystals: X···π Preferred over X···O/N?

Sulphonamides have been one of the major pharmaceutical compound classes since their introduction in the 1930s. Co-crystallisation of sulphonamides with halogen bonding (XB) might lead to a new class of pharmaceutical-relevant co-crystals. We present the synthesis and structural analysis of seven new co-crystals of simple sulphonamides N-methylbenzenesulphonamide (NMBSA), N-phenylmethanesulphonamide (NPMSA), and N-phenylbenzenesulphonamide (BSA), as well as of an anti-diabetic agent Chlorpropamide (CPA), with the model XB-donors 1,4-diiodotetrafluorobenzene (14DITFB), 1,4-dibromotetrafluorobenzene (14DBTFB), and 1,2-diiodotetrafluorobenzene (12DITFB). In the reported co-crystals, X···O/N bonds do not represent the most common intermolecular interaction. Against our rational design expectations and the results of our statistical CSD analysis, the normally less often present X···π interaction dominates the crystal packing. Furthermore, the general interaction pattern in model sulphonamides and the CPA multicomponent crystals differ, mainly due to strong hydrogen bonds blocking possible interaction sites.

Like many other modern pharmaceuticals, some sulphonamides lack bioavailability [26,27]. One well-documented way to overcome this problem and simultaneously improve other macroscopic properties is co-crystallisation [28][29][30][31]. By profoundly investigating interaction patterns, general patterns of sulphonamides might be found. This is based on the well-known synthon theory, which despite its failures is still the starting point of rational design and could lead not only to one co-crystal but to a whole new class of pharmaceutical-relevant co-crystals.
Halogen bonds (XBs), an attractive interaction of a halogen moiety's (-Cl, -Br, -I) partially positive charged σ-hole with a partially negative charged area, is along with hydrogen bonding one of the most important anisotropic intermolecular interactions [32]. There are numerous XBs; for example, strong XBs are formed with ions and oxygen and nitrogen moieties. XBs formed between two halogens are categorised into Type I and II based on the geometrical parameters [33]. In some cases, the so-called Quasi Type I/II can occur [34]. Some rare examples of XBs with aromatic π-systems have been reported [35][36][37][38].

Crystal Structure of NMBSA-14DITFB (1:1), 1
The NMBSA-14DITFB (1:1) co-crystal, 1, crystallises in the orthorhombic space group Pna21 with NMBSA and 14DITFB in a 1:1 ratio (Figure 1a). These form alternating layers along the ab-plane in a simple ABAB motif (Figure 1b). The sulphonamide layer is interconnected via strong and weak hydrogen bonds. Predominantly, a chain motif is established between the amine and the sulphone group (d(O2···H1) = 2.1(1) Å, d(O2···N1) = 3.009(7) Å). The 14DITFB layers are only loosely connected with weak F···π interactions in a herringbone pattern. The layers interact via two independent halogen bonds. On one side, there is an XB (C8-I1···N1) with the free nitrogen electron pair. It is short (d = 3.057(6) Å) and straight (∢ = 179.8(2)°), both of which are signs of strong interactions. On the other side is a halogen bond between iodine and the π-system. It is relatively weak with a distance of d(I2···cg) = 4.045 Å and an angle of ∢(C11-I2···cg) = 166.0°. = 179.8(2) • ), both of which are signs of strong interactions. On the other side is a halogen bond between iodine and the π-system. It is relatively weak with a distance of d(I2···cg) = 4.045 Å and an angle of Molecules 2023, 28, x FOR PEER REVIEW occur [34]. Some rare examples of XBs with aromatic π-systems have been rep 38]. These X···π interactions are weaker than the others mentioned becau relatively widespread electron density along the π-system. This work presents a series of rationally designed co-crystalline systems sulphonamides with halogen-bonding donors (Scheme 1). Selected survey ob from the simplest archetypal sulphonamides to their pharmaceutically active CPA. The simplest sulphonamides are N-methylbenzenesulphonamide (NMBS phenylmethanesulphonamide (NPMSA) [40,41], and N-phenylbenzenesulp (BSA) [42]. They are derivates only substituted by methyl and phenyl moieties, nonpolar and sterically manageable. On the other hand, there is Chlorpropam [12], which has been used as an anti-diabetic agent. CPA is more complex and the sulphonamide subcategory sulphonylureas, which inhibit a urea-like moie used to treat diabetes. It has six polymorphic modifications [43,44] and one crystal with 4,4′-dipyridyl [45]. The coformers, 1,4-diiodotetrafluorobenzene 1,4-dibromotetrafluorobenzene (14DBTFB), and 1,2-diiodotetrafluorobenzene are model XB coformers used in various studies to obtain multicomponent syste on the obtained crystal structures, a topological analysis of intermolecular in with a primary emphasis on different types of halogen bonding is carried out. Scheme 1. Molecular structures of used substances.
The structure was solved with a disordered iodine atom (87:13). The disorder is based on different possible interactions with the π-system. Only the iodine atom was refined separately since the whole molecule would have required a lot of restrains.  The CPA-1,4DITFB (2:1) co-crystal, 5, crystallises in a monoclinic space group, P2 1 /n, with CPA and 14DITFB in a 2:1 ratio ( Figure 5a). The strongest intermolecular interaction within this structure is the HB chain pattern of the CPA molecules. The molecules' alignment regarding each other is defined by the 2 1 -screw axis going through the urea moiety of the oxygen double bond. The hydrogen atoms of the urea moiety interact with the oxygen atom of the next urea moiety, (d(H1···O3) = 1.91(4) Å, d(H2A···O3) = 2.21(4) Å), and one of the oxygen atoms of the sulphone group (d(H2A···O1) = 2.36(4) Å). These chains are interconnected via π-stacking and form zig-zag-planes. The planes are connected via 14DITFB. In the middle of 14DITFB is an inversion centre; therefore, only half of the molecule is part of the asymmetric unit. The XB distance is relatively long (d(I1A···cg) = 3.626 Å, 023, 28, x FOR PEER REVIEW 2 of 16 occur [34]. Some rare examples of XBs with aromatic π-systems have been reported [35][36][37][38]. These X···π interactions are weaker than the others mentioned because of the relatively widespread electron density along the π-system. This work presents a series of rationally designed co-crystalline systems of selected sulphonamides with halogen-bonding donors (Scheme 1). Selected survey objects range from the simplest archetypal sulphonamides to their pharmaceutically active derivative CPA. The simplest sulphonamides are N-methylbenzenesulphonamide (NMBSA) [39], Nphenylmethanesulphonamide (NPMSA) [40,41], and N-phenylbenzenesulphonamide (BSA) [42]. They are derivates only substituted by methyl and phenyl moieties, which are nonpolar and sterically manageable. On the other hand, there is Chlorpropamide (CPA) [12], which has been used as an anti-diabetic agent. CPA is more complex and belongs to the sulphonamide subcategory sulphonylureas, which inhibit a urea-like moiety and are used to treat diabetes. It has six polymorphic modifications [43,44] and one known cocrystal with 4,4′-dipyridyl [45]. The coformers, 1,4-diiodotetrafluorobenzene (14DITFB), 1,4-dibromotetrafluorobenzene (14DBTFB), and 1,2-diiodotetrafluorobenzene (12DITFB), are model XB coformers used in various studies to obtain multicomponent systems. Based on the obtained crystal structures, a topological analysis of intermolecular interactions with a primary emphasis on different types of halogen bonding is carried out. Scheme 1. Molecular structures of used substances.
The structure was solved with a disordered bromine atom (53:47). The disorder is based on different possible interactions with the π-system, and the higher disorder here compared to 5 is a direct consequence of the weaker XBs. Only the bromine atom was refined separately since a refinement of the whole molecule requires a lot of restrains, although in this case, the ellipsoids of F1 and F2 also indicate disorder.  The CPA-12DITFB (2:1) co-crystal, 7, crystallises in a monoclinic space group C2/c with CPA and 12DITFB in a 2:1 ratio (Figure 7). Strong and weak HBs hold the CPA zigzag-plane structure together, and π-stacking is the same as in the crystal structures 5 and 6. In contrast, here the space between the layers is filled with 12DITFB, which interacts via weak XBs with the π-system of CPA (d(I1···cg) = 4.168 Å, ∢(C11-I1···cg) = 155.4°). The 12DITFB is locked in the centre in place by the rotational axis and cannot move in any way without losing symmetry. Therefore, it cannot move closer towards the π-systems of two CPA molecules of the lattice structure. Again, the long XBs result from symmetry-related needs and the slight geometrical mismatch. The structure was solved with a disordered iodine atom (87:13). The disorder is based on different possible interactions with the π-system. Only the iodine atom was refined separately since the whole molecule would have required a lot of restrains.
The structure was solved with a disordered bromine atom (53:47). The disorder is based on different possible interactions with the π-system, and the higher disorder here compared to 5 is a direct consequence of the weaker XBs. Only the bromine atom was refined separately since a refinement of the whole molecule requires a lot of restrains, although in this case, the ellipsoids of F1 and F2 also indicate disorder.  The CPA-12DITFB (2:1) co-crystal, 7, crystallises in a monoclinic space group C2/c with CPA and 12DITFB in a 2:1 ratio (Figure 7). Strong and weak HBs hold the CPA zigzag-plane structure together, and π-stacking is the same as in the crystal structures 5 and 6. In contrast, here the space between the layers is filled with 12DITFB, which interacts via weak XBs with the π-system of CPA (d(I1···cg) = 4.168 Å, ∢(C11-I1···cg) = 155.4°). The 12DITFB is locked in the centre in place by the rotational axis and cannot move in any way without losing symmetry. Therefore, it cannot move closer towards the π-systems of two CPA molecules of the lattice structure. Again, the long XBs result from symmetry-related needs and the slight geometrical mismatch. The structure was solved with a disordered bromine atom (53:47). The disorder is based on different possible interactions with the π-system, and the higher disorder here compared to 5 is a direct consequence of the weaker XBs. Only the bromine atom was refined separately since a refinement of the whole molecule requires a lot of restrains, although in this case, the ellipsoids of F1 and F2 also indicate disorder. The CPA-12DITFB (2:1) co-crystal, 7, crystallises in a monoclinic space group C2/c with CPA and 12DITFB in a 2:1 ratio (Figure 7). Strong and weak HBs hold the CPA zig-zag-plane structure together, and π-stacking is the same as in the crystal structures 5 and 6. In contrast, here the space between the layers is filled with 12DITFB, which interacts via weak XBs with the π-system of CPA (d(I1···cg) = 4.168 Å, Molecules 2023, 28, x FOR PEER REVIEW occur [34]. Some rare examples of XBs with aromatic 38]. These X···π interactions are weaker than the relatively widespread electron density along the π-sy This work presents a series of rationally designe sulphonamides with halogen-bonding donors (Schem from the simplest archetypal sulphonamides to their CPA. The simplest sulphonamides are N-methylbenz phenylmethanesulphonamide (NPMSA) [40,41], an (BSA) [42]. They are derivates only substituted by me nonpolar and sterically manageable. On the other ha [12], which has been used as an anti-diabetic agent. C the sulphonamide subcategory sulphonylureas, whic used to treat diabetes. It has six polymorphic modifi crystal with 4,4′-dipyridyl [45]. The coformers, 1,4-d 1,4-dibromotetrafluorobenzene (14DBTFB), and 1,2-d are model XB coformers used in various studies to obt on the obtained crystal structures, a topological ana with a primary emphasis on different types of haloge Scheme 1. Molecular structures of used substances.

Crystal Structure of NMBSA-14DITFB (1:1), 1
The NMBSA-14DITFB (1:1) co-crystal, 1, crystalli Pna21 with NMBSA and 14DITFB in a 1:1 ratio (Figur along the ab-plane in a simple ABAB motif (Figu interconnected via strong and weak hydrogen bond established between the amine and the sulphone grou = 3.009(7) Å). The 14DITFB layers are only loosely con in a herringbone pattern. The layers interact via two i side, there is an XB (C8-I1···N1) with the free nitrogen Å) and straight (∢ = 179.8(2)°), both of which are signs side is a halogen bond between iodine and the π-s distance of d(I2···cg) = 4.045 Å and an angle of ∢(C11- without losing symmetry. Therefore, it cannot move closer towards the π-systems of two CPA molecules of the lattice structure. Again, the long XBs result from symmetry-related needs and the slight geometrical mismatch.

Discussion
To give a broader context for the described XB patterns, in-depth research on intermolecular XB interactions of the three diiodotetrafluorobenzenes 12DITFB, 13DITFB, and 14DITFB in the Cambridge Structural Database (CSD) [46] has been performed. Therefore, we analysed 553 structures and categorised the halogen bonds into four major groups, which are discussed in the following section. The results are presented in Figure  8; all search parameters are listed in the Supplementary Materials. In the blue area, a total of 807 halogen bonds are depicted (583 I···N, 224 I···O). This group is the by far most populated one, which is hardly discernible since most of the points are overlapping. These interactions are the classic strong XBs, which are wellknown and obviously often described [32]. Therefore, these interactions are the ones we expected for our systems.

Discussion
To give a broader context for the described XB patterns, in-depth research on intermolecular XB interactions of the three diiodotetrafluorobenzenes 12DITFB, 13DITFB, and 14DITFB in the Cambridge Structural Database (CSD) [46] has been performed. Therefore, we analysed 553 structures and categorised the halogen bonds into four major groups, which are discussed in the following section. The results are presented in Figure 8; all search parameters are listed in the Supplementary Materials.

Discussion
To give a broader context for the described XB patterns, in-depth research on intermolecular XB interactions of the three diiodotetrafluorobenzenes 12DITFB, 13DITFB, and 14DITFB in the Cambridge Structural Database (CSD) [46] has been performed. Therefore, we analysed 553 structures and categorised the halogen bonds into four major groups, which are discussed in the following section. The results are presented in Figure  8; all search parameters are listed in the Supplementary Materials. In the blue area, a total of 807 halogen bonds are depicted (583 I···N, 224 I···O). This group is the by far most populated one, which is hardly discernible since most of the points are overlapping. These interactions are the classic strong XBs, which are wellknown and obviously often described [32]. Therefore, these interactions are the ones we expected for our systems. This work presents a series of ration sulphonamides with halogen-bonding do from the simplest archetypal sulphonam CPA. The simplest sulphonamides are Nphenylmethanesulphonamide (NPMSA) (BSA) [42]. They are derivates only substi nonpolar and sterically manageable. On [12], which has been used as an anti-diab the sulphonamide subcategory sulphony used to treat diabetes. It has six polymo crystal with 4,4′-dipyridyl [45].

Crystal Structure of NMBSA-14DITFB
The NMBSA-14DITFB (1:1) co-crysta Pna21 with NMBSA and 14DITFB in a 1:1 along the ab-plane in a simple ABAB interconnected via strong and weak hyd established between the amine and the su = 3.009(7) Å). The 14DITFB layers are only in a herringbone pattern. The layers inter side, there is an XB (C8-I1···N1) with the fr Å) and straight (∢ = 179.8(2)°), both of wh side is a halogen bond between iodine distance of d(I2···cg) = 4.045 Å and an ang In the blue area, a total of 807 halogen bonds are depicted (583 I···N, 224 I···O). This group is the by far most populated one, which is hardly discernible since most of the points are overlapping. These interactions are the classic strong XBs, which are well-known and obviously often described [32]. Therefore, these interactions are the ones we expected for our systems.
The area of XB interactions with aromatic systems is more extensive and diverse. Therefore, to increase the comparability, only C6 aromatic systems were considered. The distance (d), as well as the angle ( Scheme 1. Molecular structures of used substances. 14DITFB (1:1), 1 The NMBSA-14DITFB (1:1) co-crystal, 1, crystallises in the orthorhombic spa Pna21 with NMBSA and 14DITFB in a 1:1 ratio (Figure 1a). These form alternati along the ab-plane in a simple ABAB motif (Figure 1b). The sulphonamide interconnected via strong and weak hydrogen bonds. Predominantly, a chain established between the amine and the sulphone group (d(O2···H1) = 2.1(1) Å, d = 3.009(7) Å). The 14DITFB layers are only loosely connected with weak F···π int in a herringbone pattern. The layers interact via two independent halogen bonds side, there is an XB (C8-I1···N1) with the free nitrogen electron pair. It is short (d = Å) and straight (∢ = 179.8(2)°), both of which are signs of strong interactions. On side is a halogen bond between iodine and the π-system. It is relatively wea distance of d(I2···cg) = 4.045 Å and an angle of ∢(C11-I2···cg) = 166.0°.

Crystal Structure of NMBSA-
), is measured relative to the centre of gravity (cg) for the same reason. The broadest category includes solely the I···cg interactions, without any XBs with a nitrogen or an oxygen (I···cg_w/o) atom being involved. The 101 I···cg interactions reach from 3.4 Å to 4.5 Å and from 50 • to 180 • . A cut-off was made at 4.5 Å since interactions at this point are almost impossible. The subgroup I···cg_opp within this category contains 23 XB interactions of DITFBs, which on the opposing iodine are interacting with nitrogen or oxygen. We had the hypothesis that they might behave with less direction and be more focused on the I···O/N site; hence, the stronger interaction with the electron-rich moieties should dominate the interaction pattern. But, interestingly, based on the scatterplot, no difference is noticeable compared to the I···cg_w/o, and the interactions are distributed in the whole green area. In contrast to that, I···cg_con indicates interactions where the same iodine entity shares both I···O/N and I···cg. From the 70 XB interactions found in the database, 62 are mostly caused by symmetry between "con" and "opp". However, this subgroup, as indicated by the black line, is almost solely found in the region with longer distances and a lower angle. This is understandable considering the competing strong XB acceptor. Overall, the ratio between I···O/N and I···cg given in the literature is 4:1 (807:194). On the other hand, a more rigorous view on I···cg would move the ratio even further in favour of I···O/N.
The nine XBs in the presented structures 1-7 are plotted as red stars in the scatterplot above and summarised in Table 1 together with the van der Waals radii (vdW) [47] for respective interactions. Three of these XBs are I···O/N and fit very well into analogue literature interactions (blue area). The remaining six interactions are I···cg_w/o or I···cg_opp interactions (green area). They are within the expected area, but all of them have a relatively high angle, and the XBs from 2-6 also have a relatively short interaction distance. from the simplest archetypal sulphonamides to their pharmaceutically active deriva CPA. The simplest sulphonamides are N-methylbenzenesulphonamide (NMBSA) [39 phenylmethanesulphonamide (NPMSA) [40,41], and N-phenylbenzenesulphonam (BSA) [42]. They are derivates only substituted by methyl and phenyl moieties, which nonpolar and sterically manageable. On the other hand, there is Chlorpropamide (C [12], which has been used as an anti-diabetic agent. CPA is more complex and belong the sulphonamide subcategory sulphonylureas, which inhibit a urea-like moiety and used to treat diabetes. It has six polymorphic modifications [43,44] and one known crystal with 4,4′-dipyridyl [45]. The coformers, 1,4-diiodotetrafluorobenzene (14DIT 1,4-dibromotetrafluorobenzene (14DBTFB), and 1,2-diiodotetrafluorobenzene (12DIT are model XB coformers used in various studies to obtain multicomponent systems. B on the obtained crystal structures, a topological analysis of intermolecular interact with a primary emphasis on different types of halogen bonding is carried out. Scheme 1. Molecular structures of used substances.

Crystal Structure of NMBSA-14DITFB (1:1), 1
The NMBSA-14DITFB (1:1) co-crystal, 1, crystallises in the orthorhombic space gr Pna21 with NMBSA and 14DITFB in a 1:1 ratio (Figure 1a). These form alternating la along the ab-plane in a simple ABAB motif (Figure 1b). The sulphonamide laye interconnected via strong and weak hydrogen bonds. Predominantly, a chain mot established between the amine and the sulphone group (d(O2···H1) = 2.1(1) Å, d(O2·· = 3.009(7) Å). The 14DITFB layers are only loosely connected with weak F···π interact in a herringbone pattern. The layers interact via two independent halogen bonds. On side, there is an XB (C8-I1···N1) with the free nitrogen electron pair. It is short (d = 3.05 Å) and straight (∢ = 179.8(2)°), both of which are signs of strong interactions. On the o side is a halogen bond between iodine and the π-system. It is relatively weak wi distance of d(I2···cg) = 4.045 Å and an angle of ∢(C11-I2···cg) = 166.0°. The area of XB interactions with aromatic systems is more extensive and diverse. Therefore, to increase the comparability, only C6 aromatic systems were considered. The distance (d), as well as the angle (∢), is measured relative to the centre of gravity (cg) for the same reason. The broadest category includes solely the I···cg interactions, without any XBs with a nitrogen or an oxygen (I···cg_w/o) atom being involved. The 101 I···cg interactions reach from 3.4 Å to 4.5 Å and from 50° to 180°. A cut-off was made at 4.5 Å since interactions at this point are almost impossible. The subgroup I···cg_opp within this category contains 23 XB interactions of DITFBs, which on the opposing iodine are interacting with nitrogen or oxygen. We had the hypothesis that they might behave with less direction and be more focused on the I···O/N site; hence, the stronger interaction with the electron-rich moieties should dominate the interaction pattern. But, interestingly, based on the scatterplot, no difference is noticeable compared to the I···cg_w/o, and the interactions are distributed in the whole green area. In contrast to that, I···cg_con indicates interactions where the same iodine entity shares both I···O/N and I···cg. From the 70 XB interactions found in the database, 62 are mostly caused by symmetry between "con" and "opp". However, this subgroup, as indicated by the black line, is almost solely found in the region with longer distances and a lower angle. This is understandable considering the competing strong XB acceptor. Overall, the ratio between I···O/N and I···cg given in the literature is 4 :1 (807:194). On the other hand, a more rigorous view on I···cg would move the ratio even further in favour of I···O/N.
The nine XBs in the presented structures 1-7 are plotted as red stars in the scatterplot above and summarised in Table 1 together with the van der Waals radii (vdW) [47] for respective interactions. Three of these XBs are I···O/N and fit very well into analogue literature interactions (blue area). The remaining six interactions are I···cg_w/o or I···cg_opp interactions (green area). They are within the expected area, but all of them have a relatively high angle, and the XBs from 2-6 also have a relatively short interaction distance.
Within this study, the co-crystallisation experiments with the basic sulphonamides were performed first, resulting in structures 1-4. These structures share I···O/N and I···cg equally, slightly overrepresenting the latter compared to the literature. Co-crystallisation experiments on a real-world example, namely CPA, followed to elucidate if the same result will occur for a more complex sulphonamide system. Interestingly, a strong I···O/N interaction was not formed in either of the resulting structures, 5-7. At this point, we began an in-depth analysis of the structures to clarify why the lessons learned from the smallmodel molecules are not transferable to the larger one and if there is a reason why I···cg might be stronger than I···O/N. Newly synthesised compounds 2 and 3 both consist of the same entities of NPMSA and 14DITFB in different ratios, a phenomenon, which does not occur often for co-crystals.
The area of XB interactions with aromatic systems is more extensive and diverse. Therefore, to increase the comparability, only C6 aromatic systems were considered. The distance (d), as well as the angle (∢), is measured relative to the centre of gravity (cg) for the same reason. The broadest category includes solely the I···cg interactions, without any XBs with a nitrogen or an oxygen (I···cg_w/o) atom being involved. The 101 I···cg interactions reach from 3.4 Å to 4.5 Å and from 50° to 180°. A cut-off was made at 4.5 Å since interactions at this point are almost impossible. The subgroup I···cg_opp within this category contains 23 XB interactions of DITFBs, which on the opposing iodine are interacting with nitrogen or oxygen. We had the hypothesis that they might behave with less direction and be more focused on the I···O/N site; hence, the stronger interaction with the electron-rich moieties should dominate the interaction pattern. But, interestingly, based on the scatterplot, no difference is noticeable compared to the I···cg_w/o, and the interactions are distributed in the whole green area. In contrast to that, I···cg_con indicates interactions where the same iodine entity shares both I···O/N and I···cg. From the 70 XB interactions found in the database, 62 are mostly caused by symmetry between "con" and "opp". However, this subgroup, as indicated by the black line, is almost solely found in the region with longer distances and a lower angle. This is understandable considering the competing strong XB acceptor. Overall, the ratio between I···O/N and I···cg given in the literature is 4 :1 (807:194). On the other hand, a more rigorous view on I···cg would move the ratio even further in favour of I···O/N.
The nine XBs in the presented structures 1-7 are plotted as red stars in the scatterplot above and summarised in Table 1 together with the van der Waals radii (vdW) [47] for respective interactions. Three of these XBs are I···O/N and fit very well into analogue literature interactions (blue area). The remaining six interactions are I···cg_w/o or I···cg_opp interactions (green area). They are within the expected area, but all of them have a relatively high angle, and the XBs from 2-6 also have a relatively short interaction distance.
Within this study, the co-crystallisation experiments with the basic sulphonamides were performed first, resulting in structures 1-4. These structures share I···O/N and I···cg equally, slightly overrepresenting the latter compared to the literature. Co-crystallisation experiments on a real-world example, namely CPA, followed to elucidate if the same result will occur for a more complex sulphonamide system. Interestingly, a strong I···O/N interaction was not formed in either of the resulting structures, 5-7. At this point, we began an in-depth analysis of the structures to clarify why the lessons learned from the smallmodel molecules are not transferable to the larger one and if there is a reason why I···cg might be stronger than I···O/N. Newly synthesised compounds 2 and 3 both consist of the same entities of NPMSA and 14DITFB in different ratios, a phenomenon, which does not occur often for co-crystals.
The area of XB interactions with aromatic systems is more extensive and diverse. Therefore, to increase the comparability, only C6 aromatic systems were considered. The distance (d), as well as the angle (∢), is measured relative to the centre of gravity (cg) for the same reason. The broadest category includes solely the I···cg interactions, without any XBs with a nitrogen or an oxygen (I···cg_w/o) atom being involved. The 101 I···cg interactions reach from 3.4 Å to 4.5 Å and from 50° to 180°. A cut-off was made at 4.5 Å since interactions at this point are almost impossible. The subgroup I···cg_opp within this category contains 23 XB interactions of DITFBs, which on the opposing iodine are interacting with nitrogen or oxygen. We had the hypothesis that they might behave with less direction and be more focused on the I···O/N site; hence, the stronger interaction with the electron-rich moieties should dominate the interaction pattern. But, interestingly, based on the scatterplot, no difference is noticeable compared to the I···cg_w/o, and the interactions are distributed in the whole green area. In contrast to that, I···cg_con indicates interactions where the same iodine entity shares both I···O/N and I···cg. From the 70 XB interactions found in the database, 62 are mostly caused by symmetry between "con" and "opp". However, this subgroup, as indicated by the black line, is almost solely found in the region with longer distances and a lower angle. This is understandable considering the competing strong XB acceptor. Overall, the ratio between I···O/N and I···cg given in the literature is 4 :1 (807:194). On the other hand, a more rigorous view on I···cg would move the ratio even further in favour of I···O/N.
The nine XBs in the presented structures 1-7 are plotted as red stars in the scatterplot above and summarised in Table 1 together with the van der Waals radii (vdW) [47] for respective interactions. Three of these XBs are I···O/N and fit very well into analogue literature interactions (blue area). The remaining six interactions are I···cg_w/o or I···cg_opp interactions (green area). They are within the expected area, but all of them have a relatively high angle, and the XBs from 2-6 also have a relatively short interaction distance.
Within this study, the co-crystallisation experiments with the basic sulphonamides were performed first, resulting in structures 1-4. These structures share I···O/N and I···cg equally, slightly overrepresenting the latter compared to the literature. Co-crystallisation experiments on a real-world example, namely CPA, followed to elucidate if the same result will occur for a more complex sulphonamide system. Interestingly, a strong I···O/N interaction was not formed in either of the resulting structures, 5-7. At this point, we began an in-depth analysis of the structures to clarify why the lessons learned from the smallmodel molecules are not transferable to the larger one and if there is a reason why I···cg might be stronger than I···O/N.  Newly synthesised compounds 2 and 3 both consist of the same entities of NPMSA and 14DITFB in different ratios, a phenomenon, which does not occur often for co-crystals.
occur [34]. Some rare examples of XBs with aromatic π-systems have been reported [35][36][37][38]. These X···π interactions are weaker than the others mentioned because of the relatively widespread electron density along the π-system. This work presents a series of rationally designed co-crystalline systems of selected sulphonamides with halogen-bonding donors (Scheme 1). Selected survey objects range from the simplest archetypal sulphonamides to their pharmaceutically active derivative CPA. The simplest sulphonamides are N-methylbenzenesulphonamide (NMBSA) [39], Nphenylmethanesulphonamide (NPMSA) [40,41], and N-phenylbenzenesulphonamide (BSA) [42]. They are derivates only substituted by methyl and phenyl moieties, which are nonpolar and sterically manageable. On the other hand, there is Chlorpropamide (CPA) [12], which has been used as an anti-diabetic agent. CPA is more complex and belongs to the sulphonamide subcategory sulphonylureas, which inhibit a urea-like moiety and are used to treat diabetes. It has six polymorphic modifications [43,44] and one known cocrystal with 4,4′-dipyridyl [45]. The coformers, 1,4-diiodotetrafluorobenzene (14DITFB), 1,4-dibromotetrafluorobenzene (14DBTFB), and 1,2-diiodotetrafluorobenzene (12DITFB), are model XB coformers used in various studies to obtain multicomponent systems. Based on the obtained crystal structures, a topological analysis of intermolecular interactions with a primary emphasis on different types of halogen bonding is carried out. Scheme 1. Molecular structures of used substances.

Crystal Structure of NMBSA-14DI
The NMBSA-14DITFB (1:1) co-c Pna21 with NMBSA and 14DITFB in along the ab-plane in a simple AB interconnected via strong and weak established between the amine and t = 3.009(7) Å). The 14DITFB layers are in a herringbone pattern. The layers side, there is an XB (C8-I1···N1) with Å) and straight (∢ = 179.8(2)°), both o side is a halogen bond between iod distance of d(I2···cg) = 4.045 Å and an cg = 166.0 Molecules 2023, 28, x FOR PEER REVIEW occur [34]. Some rare examples of XBs with aromatic π-system 38]. These X···π interactions are weaker than the others relatively widespread electron density along the π-system. This work presents a series of rationally designed co-cry sulphonamides with halogen-bonding donors (Scheme 1). Se from the simplest archetypal sulphonamides to their pharma CPA. The simplest sulphonamides are N-methylbenzenesulph phenylmethanesulphonamide (NPMSA) [40,41], and N-ph (BSA) [42]. They are derivates only substituted by methyl and nonpolar and sterically manageable. On the other hand, ther [12], which has been used as an anti-diabetic agent. CPA is m the sulphonamide subcategory sulphonylureas, which inhibit used to treat diabetes. It has six polymorphic modifications crystal with 4,4′-dipyridyl [45]. The coformers, 1,4-diiodotetr 1,4-dibromotetrafluorobenzene (14DBTFB), and 1,2-diiodotetr are model XB coformers used in various studies to obtain mult on the obtained crystal structures, a topological analysis of with a primary emphasis on different types of halogen bondin Scheme 1. Molecular structures of used substances.

Crystal Structure of NMBSA-14DITFB (1:1), 1
The NMBSA-14DITFB (1:1) co-crystal, 1, crystallises in the Pna21 with NMBSA and 14DITFB in a 1:1 ratio (Figure 1a). Th along the ab-plane in a simple ABAB motif (Figure 1b). T interconnected via strong and weak hydrogen bonds. Predo established between the amine and the sulphone group (d(O2 = 3.009(7) Å). The 14DITFB layers are only loosely connected w in a herringbone pattern. The layers interact via two independ side, there is an XB (C8-I1···N1) with the free nitrogen electron Å) and straight (∢ = 179.8(2)°), both of which are signs of stron side is a halogen bond between iodine and the π-system. This work presents a series of r sulphonamides with halogen-bondin from the simplest archetypal sulpho CPA. The simplest sulphonamides a phenylmethanesulphonamide (NPM (BSA) [42]. They are derivates only s nonpolar and sterically manageable [12], which has been used as an antithe sulphonamide subcategory sulph used to treat diabetes. It has six pol crystal with 4,4′-dipyridyl [45]. The 1,4-dibromotetrafluorobenzene (14D are model XB coformers used in vario on the obtained crystal structures, a with a primary emphasis on differen Scheme 1. Molecular structures of used s

Crystal Structure of NMBSA-14DI
The NMBSA-14DITFB (1:1) co-c Pna21 with NMBSA and 14DITFB in along the ab-plane in a simple AB interconnected via strong and weak established between the amine and t = 3.009(7) Å). The 14DITFB layers are in a herringbone pattern. The layers side, there is an XB (C8-I1···N1) with Å) and straight (∢ = 179.8(2)°), both o side is a halogen bond between iod distance of d(I2···cg) = 4.045 Å and an Molecules 2023, 28, x FOR PEER REVIEW occur [34]. Some rare examples of XBs with aromatic π-syste 38]. These X···π interactions are weaker than the others relatively widespread electron density along the π-system. This work presents a series of rationally designed co-cry sulphonamides with halogen-bonding donors (Scheme 1). Se from the simplest archetypal sulphonamides to their pharm CPA. The simplest sulphonamides are N-methylbenzenesulp phenylmethanesulphonamide (NPMSA) [40,41], and N-ph (BSA) [42]. They are derivates only substituted by methyl and nonpolar and sterically manageable. On the other hand, ther [12], which has been used as an anti-diabetic agent. CPA is m the sulphonamide subcategory sulphonylureas, which inhibi used to treat diabetes. It has six polymorphic modifications crystal with 4,4′-dipyridyl [45]. The coformers, 1,4-diiodotet 1,4-dibromotetrafluorobenzene (14DBTFB), and 1,2-diiodotet are model XB coformers used in various studies to obtain mul on the obtained crystal structures, a topological analysis of with a primary emphasis on different types of halogen bondi Scheme 1. Molecular structures of used substances. occur [34]. Some rare examples of X 38]. These X···π interactions are w relatively widespread electron densi This work presents a series of r sulphonamides with halogen-bondin from the simplest archetypal sulpho CPA. The simplest sulphonamides a phenylmethanesulphonamide (NPM (BSA) [42]. They are derivates only s nonpolar and sterically manageable [12], which has been used as an antithe sulphonamide subcategory sulph used to treat diabetes. It has six pol crystal with 4,4′-dipyridyl [45]. The 1,4-dibromotetrafluorobenzene (14D are model XB coformers used in vario on the obtained crystal structures, a with a primary emphasis on differen Scheme 1. Molecular structures of used s

Crystal Structure of NMBSA-14DI
The NMBSA-14DITFB (1:1) co-c Pna21 with NMBSA and 14DITFB in along the ab-plane in a simple AB interconnected via strong and weak established between the amine and t = 3.009 (7)  occur [34]. Some rare examples of X 38]. These X···π interactions are w relatively widespread electron densi This work presents a series of r sulphonamides with halogen-bondin from the simplest archetypal sulpho CPA. The simplest sulphonamides a phenylmethanesulphonamide (NPM (BSA) [42]. They are derivates only s nonpolar and sterically manageable [12], which has been used as an antithe sulphonamide subcategory sulph used to treat diabetes. It has six pol crystal with 4,4′-dipyridyl [45]. The 1,4-dibromotetrafluorobenzene (14D are model XB coformers used in vario on the obtained crystal structures, a with a primary emphasis on differen Scheme 1. Molecular structures of used s

Crystal Structure of NMBSA-14DI
The NMBSA-14DITFB (1:1) co-c Pna21 with NMBSA and 14DITFB in along the ab-plane in a simple AB interconnected via strong and weak established between the amine and t = 3.009 (7)  occur [34]. Some rare examples of X 38]. These X···π interactions are w relatively widespread electron densi This work presents a series of r sulphonamides with halogen-bondin from the simplest archetypal sulpho CPA. The simplest sulphonamides a phenylmethanesulphonamide (NPM (BSA) [42]. They are derivates only s nonpolar and sterically manageable [12], which has been used as an antithe sulphonamide subcategory sulph used to treat diabetes. It has six pol crystal with 4,4′-dipyridyl [45]. The 1,4-dibromotetrafluorobenzene (14D are model XB coformers used in vario on the obtained crystal structures, a with a primary emphasis on differen Scheme 1. Molecular structures of used s

Crystal Structure of NMBSA-14DI
The NMBSA-14DITFB (1:1) co-c Pna21 with NMBSA and 14DITFB in along the ab-plane in a simple AB interconnected via strong and weak established between the amine and t = 3.009 (7)  occur [34]. Some rare examples of X 38]. These X···π interactions are w relatively widespread electron densi This work presents a series of r sulphonamides with halogen-bondin from the simplest archetypal sulpho CPA. The simplest sulphonamides a phenylmethanesulphonamide (NPM (BSA) [42]. They are derivates only s nonpolar and sterically manageable [12], which has been used as an antithe sulphonamide subcategory sulph used to treat diabetes. It has six pol crystal with 4,4′-dipyridyl [45]. The 1,4-dibromotetrafluorobenzene (14D are model XB coformers used in vario on the obtained crystal structures, a with a primary emphasis on differen Scheme 1. Molecular structures of used s

Crystal Structure of NMBSA-14DI
The NMBSA-14DITFB (1:1) co-c Pna21 with NMBSA and 14DITFB in along the ab-plane in a simple AB interconnected via strong and weak established between the amine and t = 3.009(7) Å). The 14DITFB layers are in a herringbone pattern. The layers side, there is an XB (C8-I1···N1) with Å) and straight (∢ = 179. 8 Within this study, the co-crystallisation experiments with the basic sulphonamides were performed first, resulting in structures 1-4. These structures share I···O/N and I···cg equally, slightly overrepresenting the latter compared to the literature. Co-crystallisation experiments on a real-world example, namely CPA, followed to elucidate if the same result will occur for a more complex sulphonamide system. Interestingly, a strong I···O/N interaction was not formed in either of the resulting structures, 5-7. At this point, we began an in-depth analysis of the structures to clarify why the lessons learned from the small-model molecules are not transferable to the larger one and if there is a reason why I···cg might be stronger than I···O/N. Newly synthesised compounds 2 and 3 both consist of the same entities of NPMSA and 14DITFB in different ratios, a phenomenon, which does not occur often for co-crystals. In some sense, it can be seen as a polymorphic behaviour. Similar to known examples of disappearing polymorphs [48,49], it was impossible to reproduce 3 in any possible way, which shows that it is disfavoured. Both structures have an intermolecular interaction with the sulphone oxygen moiety, but while in 3 both iodines of the 14DITFB are symmetry-equivalent, in 2 the second iodine interacts with a π-system. This comes from the significantly stronger I···O. It is likely that in the process of lattice formation, after forming this bond, it is sterically hindered since it needs to be elongated and rotated relative to the sulphone moiety. Therefore, the next-best option is forming an XB with the π-system favoured, leading to structure 2. In contrast, co-crystal structures of CPA (5)(6)(7) show only XBs of the I···cg; CPA forming zig-zag-planes which are intercalated with the halogen bond donors naturally occurs for these structures. The backbone of these planes are strong hydrogen bond chains of the urea moiety, which are well known in the literature [50][51][52]. However, the intermediate spaces seem to be somewhat larger than ideal for the halo-benzenes. For structures 5 and 6 it results in a longer I···cg bond than necessary, since the 14DITFB and 14DBTFB are secured by symmetry. For 7 the situation is slightly different. The iodines are not in a para but in an ortho position, and the aromatic centres are in a far-from-ideal position, resulting in the longest XB (d(I1···cg) = 4.168 Å).
Let us go back to the initial thought that XBs in sulphonamide systems might prefer π-systems over O/N-moieties as acceptors. More realistically, the HBs are stronger and, therefore, the predominant building blocks are either catameric structures (1, 4-7) or dimeric structures (2, 3). The halogens take what was left, following Ostwald's rule of stages [53]. So XBs with π-systems have become a common interaction within the investigated structures against our expectations based on statistical knowledge and model sulphonamide co-crystal structures.   Pure-phase and single crystals of 3 suitable for SCXRD were synthesised by dissolving NPMSA (10 mg, 58 µmol) and 14DITFB (12 mg, 30 µmol) in 1 mL of acetonitrile. Clear, colourless block-shaped crystals were obtained after several days via slow evaporation at room temperature. Phase 3 could not be reproduced under the same or several different conditions. All attempts led to either 2 or a mixture of the base components.

Conclusions
This study has presented four new co-crystal structures of archetypal sulphonamides (1-4) and three co-crystal structures of the pharmaceutically used CPA (5-7). All presented structures exhibit halogen bonds with para-or ortho-substituted halogen benzene derivatives, but against prior expectations based on statistical analysis and model sulphonamides, X···O/N was not formed in CPA multicomponent systems, but X···π XBs were. This is not a sign of XBs favouring aromatic systems over these strong Lewis bases but rather a consequence of competing hydrogen bonds (HBs). The sulphonamides formed strong HB dimers and catamers with O/N, interacting with multiple sites. Therefore, XBs fall behind and interact with the aromatic π-systems instead. In addition, some X···π XBs are unusually long, which is caused by symmetry and rigid sulphonamide grids.